Enkephalin analogues

ABSTRACT

The present invention relates to dipeptide enkephalin analogues of Formula (I) and their tautomers, ionic forms and pharmaceutically acceptable salts, and their use in medicine, in particular as opioid agonists.

This application was filed under 35 USC §371 based on PCT/IB2012/053327 which was filed Jun. 29, 2012 which claims priority from US Provisional Application 61/507,280 filed Jul. 13, 2011.

The invention described herein relates to peptide analogue compounds and the pharmaceutically acceptable salts of such compounds. The invention also relates to the processes for the preparation of the compounds, compositions containing the compounds, and the uses of such compounds and salts in treating diseases or conditions associated with opioid activity. More specifically the invention relates to the compounds and their salts useful as opioid agonists.

BACKGROUND

The opioid receptor family, consisting of μ-, δ- and κ-receptors, is a member of the rhodopsin subfamily in the superfamily of G-protein coupled receptors (GPCRs). These receptors share extensive structural and sequence homology (˜60% amino acid identity) but recognise structurally diverse ligands comprising exogenous opiates, endogenous peptides and synthetic peptidic and non-peptidic ligands (Waldhoer et al., Annu. Rev. Biochem (2004) 73: 953-990). Opiates e.g. morphine and synthetic opioids e.g. fentanyl, acting through their activity at the μ-opioid receptor are some of the most potent analgesic drugs for moderate to severe pain conditions. However, for chronic pain conditions, their widespread use is limited by side effects such as constipation, respiratory depression, nausea, sedation, physical dependence and the potential for addiction. Opioid receptors are widely expressed in the central nervous system (CNS) and periphery of many species including man. Opioid receptors have been localised on peripheral processes of sensory neurones in animals and humans (Stein et al., 2003). Most opiates and opioids mediate their analgesic effects via peripheral, spinal and supraspinal receptors. However recent preclinical and clinical studies, using either local administration or compounds with special physicochemical and/or pharmacokinetic properties to restrict their action to the periphery, suggest that analgesia can be achieved via peripheral μ-opioid receptors (MORs) alone (Bileviciute-Ljungar et al., J. Pharmacol. Exp. Ther. (2006) 317: 220-227; Gordon et al., Drug disc. Today: Ther. Strat. (2009) in press; He et al., J. Pain (2009) 10: 369-379; Koppert et al., Anesth Analg (1999) 88: 117-122; Oeltjenbruns and Schafer, Curr. Pain Headache Reports 2005; 9: 36-44; Stein et al., Nat. Med. (2003) 9: 1003-1008; Stein and Lang, Curr. Opin. Pharmacol. (2009) 9: 1-6; Wenk et al., J. Neurophysiol. (2006) 95: 2083-2097). In general, efficacy is achieved under conditions of ongoing inflammation. This is consistent with the observation of increased primary afferent MORs in inflammatory models of pain and with the expression of MORs on inflammation-attracted immune cells. Frakefamide, a synthetic μ-opioid receptor agonist demonstrated efficacy in a dental pain study (Becktor et al., abstract from 2002 World Congress on Pain) at doses that did not elicit respiratory depression (Österlund Modalen et al., abstract from 2002 World Congress on Pain; Österlund Modalen et al., 2005; Anesth Analg, 100: 713-717). Synthetic compounds acting specifically through peripheral μ-opioid receptors provide the potential to effectively manage pain without the centrally-mediated adverse effects of drugs like morphine, e.g. Current Pharmaceutical Design, 2004 (10), 743-757; Ther Clin Risk Manag. 2005 December; 1(4): 279-297.

Replacement of Tyrosine with dimethylTyrosine is described in Bioorganic & Medicinal Chemistry Letters 17 (2007) 2043-2046, European Journal of Pharmacology, Volume 302, Issues 1-3, 29 Apr. 1996, Pages 37-42.

Various peptides and analogues thereof with biological activity, including some with opioid activity, are disclosed in:

-   Schiler et al in Eur. J. Med. Chem. 35 (2000) 895-901; -   Szeto et al, JPET 298:57-61, 2001; -   Bajusz et al, FEBS Letters January 1980, 110(1), 85-87 -   Ogawa et al, Peptide Science 2001, 101-104; -   Konopinska, Polish J. Chem (1994), 68(7) 1437-9; -   Fancioulli et al, Eur J Endocrinology (1996) 134: 73-76; -   Giusti et al, Acta Endocrinologica (1992) 127: 205-209; -   Howlett et al, Horm. Metab. Res. 23 (1991) 341-343; -   Konopinska, Int. J. Peptide Protein Res. 35, 1990, 12-16; -   Delitala et al, J. Clin. Endocrinology and Metabolism (1989), 69(2),     356-358; -   Borges et al, J. Endocr. (1988) 116, 313-317; -   Marastoni et al, II Farmaco-Ed. Sc. vol 42 fasc 2, 125-131; -   Pastore et al, Peptides-Structures and Function, Proceedings of the     9^(th) American -   Peptide Symposium 529-532; -   Salvadori et al, Peptides, 6(Suppl 3), 1985, 127-129; -   Cervinin et al, Peptides, vol 6, 1985, 433-437; -   Marton et al, Neurohumoral Mech (1983) meeting date 1982, 303-307; -   Salvadori et al, Hoppe-Seyler's Z. Physiol. Chem. Bd 365,     S.1199-1206, October 1984; -   Castiglione, Highlights in Receptor Chemistry 1984 (publ. Elsevier),     149-168; -   Salvadori et al, Eur J Med Chem Chim Ther 1983-18, no. 6, 489-493; -   Sarto et al, Farmaco Ed. Sc. (1983) 647-652; -   Tomatis et al, Peptides 1982, 495-499; -   Salvadori et al, II Farmaco-Ed. Sc. 37(fasc 8) 514-518; -   Hermann et al, Adv. Physiol. Sci, vol 14. Endocrinology,     Neuroendocrinology, Neuropeptides-II, 333-337; -   Ronai et al, Eur. J. Pharmacology 69 (1981) 263-271; -   Okayama et al, Peptide Science 2002, Japanese Peptide Society,     69-72; -   Salvadori et al, J. Med. Chem., 1986, 29, 889-894; -   Marastoni et al, J. Med. Chem., 1987, 30, 1538-1542; -   Castiglione-Morelli et al, J. Med. Chem., 1987, 30, 2067-2073; -   Hardy et al, J. Med. Chem., 1988, 31, 960-966; -   Hardy et al, J. Med. Chem., 1989, 32, 1108-1118; -   Kharkevich et al, FEBS Letters 351 (1994) 308-301; -   Salvino et al, Bioorganic & Medicinal Chemistry Letters 5(4) 357-362     (1995); -   Dankwardt et al, Bioorganic & Medicinal Chemistry Letters 7(14)     1921-1926 (1997); -   Ogawa et al, Chem Pharm Bull 50(6) 771-780 (2002); -   Ogawa et al, J. Med. Chem., 2002, 45, 5081-5089; -   Genco et al, Int. J. Antimicrobial Agents 21 (2003) 75-78; -   Deguchi et al, JPET 310:177-184 (2004); -   Wolin et al, Bioorganic & Medicinal Chemistry, 12 (2004) 4477-4492; -   Liu et al, JPET 319:308-316 (2006); -   Suhs et al, Chem. Eur. J. 2006, 12, 8150-8157; -   Mizoguchi et al, Eur, J. Pharmacology 560 (2007) 150-159; -   Liu et al, Peptides 29 (2008) 1048-1056; -   Velu et al, J. Med. Chem. 2007, 50, 2612-2621; -   Hansen et al, European Patent Application 0 154 234; -   and Chamberland et al, U.S. Pat. No. 6,114,310.

International Patent Application PCT/IB2011/050580, filed 11 Feb. 2011, refers to peptide analogues incorporating a guanidine group as opioid agonists.

There is a need to provide new opioid receptor agonists that are good drug candidates. In particular, compounds should preferably bind potently to the μ-opioid receptor whilst showing little affinity for other receptors and show functional activity as μ-opioid receptor agonists. They should preferably be active following topical administration, and/or well absorbed from the gastrointestinal tract, and/or be injectable directly into the bloodstream, muscle, or subcutaneously, and/or be metabolically stable and possess favourable pharmacokinetic properties. When targeted against receptors in the central nervous system they should cross the blood brain barrier freely and when targeted selectively against receptors in the peripheral nervous system they should not cross the blood brain barrier. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.

SUMMARY

The present invention relates to compounds of the Formula I:

or a pharmaceutically acceptable salt thereof.

The invention is also directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention is also directed to a method of treating a disease or condition indicated for treatment with an opioid receptor agonist, particularly a μ-opioid receptor agonist, in a subject, by administering to a subject in need thereof a therapeutically effective amount of one or more of the compounds herein, or a pharmaceutically acceptable salt thereof.

Other aspects of the invention will be apparent from the remaining description and claims.

Preferably, the compounds of the present invention are potent agonists at the μ-opioid receptor, and have a suitable PK profile to enable once daily dosing. Particularly preferably, the compounds of the present invention have physical properties that minimise penetration into the CNS. Various references suggests that CNS penetration can be restricted through appropriate physiochemical properties such as lipophilicity, number of H-bond donors, polar surface area, number of charged centres (see e.g. K. M. M. Doan THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2002, Vol. 303 (3) 1029-1037 and L. Di, Expert Opinion on Drug Discovery June 2008, Vol. 3, No. 6: 677-687).

The compounds of the present invention are potentially useful in the treatment of a range of disorders where an opioid agonist is indicated, particularly pain indications. Depending on the disease and condition of the patient, the term “treatment” as used herein may include one or more of curative, palliative and prophylactic treatment.

According to the invention a compound of the present invention may be used to treat any physiological pain such as inflammatory pain, nociceptive pain, neuropathic pain, acute pain, chronic pain, musculo-skeletal pain, on-going pain, central pain, heart and vascular pain, head pain, orofacial pain. Other pain conditions which may be treated include intense acute pain and chronic pain conditions which may involve the same pain pathways driven by pathophysiological processes and as such cease to provide a protective mechanism and instead contribute to debilitating symptoms associated with a wide range of disease states.

Pain is a feature of many trauma and disease states. When a substantial injury, via disease or trauma, to body tissue occurs the characteristics of nociceptor activation are altered, this leads to hypersensitivity at the site of damage and in nearby normal tissue. In acute pain the sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is normally due to nervous system injury due to maladaptation of the afferent fibres (Woolf & Salter 2000 Science 288: 1765-1768). Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. There are a number of typical pain subtypes: 1) spontaneous pain which may be dull, burning, or stabbing; 2) pain responses to noxious stimuli are exaggerated (hyperalgesia); 3) pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Pain can be divided into a number of different areas because of differing pathophysiology, these include nociceptive, inflammatory, neuropathic pain among others. It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. Back pain, Cancer pain have both nociceptive and neuropathic components.

Nociceptive Pain

Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and sensitise the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994 Textbook of Pain 13-44). The activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for the sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey the dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to pain from strains/sprains, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, burns, myocardial infarction, acute pancreatitis, and renal colic. Also cancer related acute pain syndromes commonly due to therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormonal therapy and radiotherapy. Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to, cancer pain which may be tumour related pain, (e.g. bone pain, headache and facial pain, viscera pain) or associated with cancer therapy (e.g. postchemotherapy syndromes, chronic postsurgical pain syndromes, post radiation syndromes), back pain which may be due to herniated or ruptured intervertabral discs or abnormalities of the lumbar facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament.

Neuropathic Pain

According to the invention a compound of the present invention can potentially be used to treat neuropathic pain and the symptoms of neuropathic pain including hyperalgesia, allodynia and ongoing pain. Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (IASP definition). Nerve damage can be caused by trauma and disease and thus the term ‘neuropathic pain’ encompasses many disorders with diverse aetiologies. These include but are not limited to, Diabetic neuropathy, Post herpetic neuralgia, Back pain, Cancer neuropathy, HIV neuropathy, Phantom limb pain, Carpal Tunnel Syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia, or vitamin deficiencies. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patients quality of life (Woolf and Mannion 1999 Lancet 353: 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd 1999 Pain Supp. 6: S141-S147; Woolf and Mannion 1999 Lancet 353: 1959-1964). They include spontaneous pain, which can be continuous, or paroxysmal and abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).

Intense Acute Pain and Chronic Pain

Intense acute pain and chronic pain may involve the same pathways driven by pathophysiological processes and as such cease to provide a protective mechanism and instead contribute to debilitating symptoms associated with a wide range of disease states. Pain is a feature of many trauma and disease states. When a substantial injury, via disease or trauma, to body tissue occurs the characteristics of nociceptor activation are altered. There is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. This leads to hypersensitivity at the site of damage and in nearby normal tissue. In acute pain these mechanisms can be useful and allow for the repair processes to take place and the hypersensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is normally due to nervous system injury. This injury often leads to maladaptation of the afferent fibres (Woolf & Salter 2000 Science 288: 1765-1768). Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. There are a number of typical pain subtypes: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); 3) pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Although patients with back pain, arthritis pain, CNS trauma, or neuropathic pain may have similar symptoms, the underlying mechanisms are different and, therefore, may require different treatment strategies.

Chronic Pain

Chronic pain comprises one or more of, chronic nociceptive pain, chronic neuropathic pain, chronic inflammatory pain, breakthrough pain, persistent pain hyperalgesia, allodynia, central sensitisation, peripheral sensitisation, disinhibition and augmented facilitation.

Chronic pain includes cancer pain, e.g. cancer pain arising from malignancy, adenocarcinoma in glandular tissue, blastoma in embryonic tissue of organs, carcinoma in epithelial tissue, leukemia in tissues that form blood cells, lymphoma in lymphatic tissue, myeloma in bone marrow, sarcoma in connective or supportive tissue, adrenal cancer, AIDS-related lymphoma, anemia, bladder cancer, bone cancer, brain cancer, breast cancer, carcinoid tumour s, cervical cancer, chemotherapy, colon cancer, cytopenia, endometrial cancer, esophageal cancer, gastric cancer, head cancer, neck cancer, hepatobiliary cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, Hodgkin's disease, lymphoma, non-Hodgkin's, nervous system tumours, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, urethral cancer, bone cancer, sarcomas cancer of the connective tissue, cancer of bone tissue, cancer of blood-forming cells, cancer of bone marrow, multiple myeloma, leukaemia, primary or secondary bone cancer, tumours that metastasize to the bone, tumours infiltrating the nerve and hollow viscus, tumours near neural structures. Cancer pain also comprises visceral pain, e.g. visceral pain which arises from pancreatic cancer and/or metastases in the abdomen, somatic pain, e.g. somatic pain due to one or more of bone cancer, metastasis in the bone, postsurgical pain, sarcomas cancer of the connective tissue, cancer of bone tissue, cancer of blood-forming cells of the bone marrow, multiple myeloma, leukaemia, primary or secondary bone cancer.

Inflammatory Pain

Inflammatory conditions include acute inflammation, persistent acute inflammation, chronic inflammation, and combined acute and chronic inflammation.

Inflammatory pain includes acute inflammatory pain and/or chronic inflammatory pain wherein the chronic inflammatory pain can be pain involving both peripheral and central sensitisation and/or mixed etiology pain involving both inflammatory pain and neuropathic pain or nociceptive pain components. Inflammatory pain also comprises hyperalgesia, e.g. primary and/or secondary hyperalgesia. Additionally or alternatively the inflammatory pain can include allodynia. Inflammatory pain also comprises pain that persists beyond resolution of an underlying disorder or inflammatory condition or healing of an injury.

Inflammatory pain is pain resulting an inflammatory condition. e.g. in response to acute tissue injury due to trauma, disease e.g. an inflammatory disease, immune reaction, the presence of foreign substances, chemicals or infective particles for example micro-organisms. Inflammatory conditions can be either acute or chronic inflammation or both.

Inflammatory pain can result from an inflammatory condition due to an inflammatory disease such as inflammatory joint diseases, inflammatory connective tissue diseases, inflammatory autoimmune diseases, inflammatory myopathies, inflammatory digestive system diseases, inflammatory air way diseases, cellular immune inflammation diseases, hypersensitivities and allergies, vasular inflammation diseases, non-immune inflammatory disease, synovitis, villonodular synovitis, arthralgias, ankylosing spondylitis, spondyloarthritis, spondyloarthropathy, gout, Pagets disease, periarticular disorders such as bursitis, rheumatoid disease, rheumatoid arthritis and osteoarthritis, rheumatoid arthritis or osteoarthritis. Rheumatoid arthritis in particular, represents ongoing inflammation associated with severe pain. Arthritic pain is a form of inflammatory pain and arises from inflammation in a joint which causes both peripheral sensitization and central sensitization. Under inflammatory conditions the nociceptive system is activated by normally innocuous and nonpainful mechanical stimuli. Additionally when the joint is at rest pain is present and appears as spontaneous pain and hyperalgesia (augmented pain response on noxious stimulation and pain on normally nonpainful stimulation). Inflammatory processes in peripheral tissues lead to central sensitization in the spinal cord, which contributes to hyperalgesia and allodynia typically associated with inflammatory pain. Other types of inflammatory pain include inflammatory bowel diseases (IBD).

Other Types of Pain

Other types of pain include but are not limited to:

-   -   Musculo-skeletal disorders including but not limited to myalgia,         fibromyalgia, spondylitis, sero-negative (non-rheumatoid)         arthropathies, non-articular rheumatism, dystrophinopathy,         Glycogenolysis, polymyositis, pyomyositis;     -   Central pain or ‘thalamic pain’ as defined by pain caused by         lesion or dysfunction of the nervous system including but not         limited to central post-stroke pain, multiple sclerosis, spinal         cord injury, Parkinson's disease and epilepsy;     -   Heart and vascular pain including but not limited to angina,         myocardial infarction, mitral stenosis, pericarditis, Raynaud's         phenomenon, scleroderma, scleredoma, skeletal muscle ischemia;     -   Visceral pain, and gastrointestinal disorders. The viscera         encompasses the organs of the abdominal cavity. These organs         include the sex organs, spleen and part of the digestive system.         Pain associated with the viscera can be divided into digestive         visceral pain and non-digestive visceral pain. Commonly         encountered gastrointestinal (GI) disorders include the         functional bowel disorders (FBD) and the inflammatory bowel         diseases (IBD). These GI disorders include a wide range of         disease states that are currently only moderately controlled,         including—for FBD, gastro-esophageal reflux, dyspepsia, the         irritable bowel syndrome (IBS) and functional abdominal pain         syndrome (FAPS), and—for IBD, Crohn's disease, ileitis, and         ulcerative colitis, which all regularly produce visceral pain.         Other types of visceral pain include the pain associated with         dysmenorrhea, pelvic pain, cystitis and pancreatitis;

Head pain including but not limited to migraine, migraine with aura, migraine without aura cluster headache, tension-type headache. Orofacial pain including but not limited to dental pain, temporomandibular myofascial pain, tinnitus, hot flushes, restless leg syndrome and blocking development of abuse potential. Further pain conditions may include, back pain, bursitis, dental pain, fibromyalgia or myofacial pain, menstrual pain, migraine, neuropathic pain (including painful diabetic neuropathy), pain associated with post-herpetic neuralgia, post-operative pain, referred pain, trigeminal neuralgia, ocular pain, aural pain, visceral pain (including interstitial cystitis and IBS) and pain associated with AIDS, allodynia, burns, cancer, hyperalgesia, hypersensitisation, spinal trauma and/or degeneration and stroke.

Other conditions that may be treated with the compounds of the present invention include urogenital indications and others e.g. urinary incontinence, overactive bladder, emesis, cognitive disorders, anxiety, depression, sleeping disorders, eating disorders, movement disorders, glaucoma, psoriasis, multiple sclerosis, cerebrovascular disorders, brain injury, gastrointestinal disorders, hypertension, cardiovascular disease.

DETAILED DESCRIPTION

The present invention relates to a compound of Formula I:

or a pharmaceutically acceptable salt thereof.

The invention is also directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention is also directed to a method of treating a disease or condition indicated for treatment with an opioid receptor agonist, particularly a μ-opioid receptor agonist, in a subject, by administering to a subject in need thereof a therapeutically effective amount of one or more of the compounds herein, or a pharmaceutically acceptable salt thereof.

Other aspects of the invention will be apparent from the remaining description and claims.

Another aspect of the invention is a compound selected from 1a, 1b, 1c and 1d below:

or a pharmaceutically acceptable salt thereof.

The most preferred compounds of formula I are those specifically mentioned in the Examples below, and their pharmaceutically acceptable salts.

“Pharmaceutically acceptable salts” of the compounds of formula I include the acid addition and base addition salts (including disalts, hemisalts, etc.) thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base addition salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The compounds of the invention include compounds of formula I and salts thereof as hereinbefore defined, polymorphs, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of formula I.

It is important to realise that all the compounds of the invention may exhibit tautomeric behaviour at one or more functional groups. It is to be understood from the definitions herein that where such groups are specified, each tautormeric form is also included.

Unless otherwise specified, compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers.

It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the claimed compounds of the present invention are all stereoisomers, tautomeric and ionic (e.g. zwitterionic) forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or other derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art. [see, for example, “Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994).]

The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.

There are a number of methods by which compounds of the general formula I and their salts can be prepared which will be apparent to those skilled in the art, exemplified in the Preparations and Examples below.

Pharmaceutically acceptable salts of a compound of formula (I) may be readily prepared by mixing together solutions of the compound of formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised.

The compounds of the invention intended for pharmaceutical use may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drug agent (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any biologically inactive ingredient other than the compounds and salts of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. For example, a compound of the formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously (e.g. as a fixed dose combination), sequentially or separately in combination with one or more other drug agent.

Exemplary Additional Agents could be Selected from One or More of:

-   -   a Nav1.7 channel modulator, such as a compound disclosed in WO         2009/012242 or WO2010/079443;     -   an alternative sodium channel modulator, such as a Nav1.3         modulator (e.g. as disclosed in WO2008/118758); or a Nav1.8         modulator (e.g. as disclosed in WO 2008/135826, more         particularly         N-[6-Amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl]-1-methyl-1H-pyrazole-5-carboxamide);     -   an inhibitor of nerve growth factor signaling, such as: an agent         that binds to NGF and inhibits NGF biological activity and/or         downstream pathway(s) mediated by NGF signaling (e.g.         tanezumab), a TrkA antagonist or a p75 antagoinsist;     -   a compound which increases the levels of endocannabinoid, such         as a compound with fatty acid amid hydrolase inhibitory (FAAH)         activity, in particular those disclosed in WO 2008/047229 (e.g.         N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridine-2-yl]oxy}benzylidene)piperidene-1-carboxamide);     -   an opioid analgesic, e.g. morphine, heroin, hydromorphone,         oxymorphone, levorphanol, levallorphan, methadone, meperidine,         fentanyl, cocaine, codeine, dihydrocodeine, oxycodone,         hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone,         naltrexone, buprenorphine, butorphanol, nalbuphine or         pentazocine;     -   a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,         diclofenac, diflusinal, etodolac, fenbufen, fenoprofen,         flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen,         ketorolac, meclofenamic acid, mefenamic acid, meloxicam,         nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,         oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac,         tolmetin or zomepirac;     -   a barbiturate sedative, e.g. amobarbital, aprobarbital,         butabarbital, butabital, mephobarbital, metharbital,         methohexital, pentobarbital, phenobartital, secobarbital,         talbutal, theamylal or thiopental;     -   a benzodiazepine having a sedative action, e.g.         chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam,         oxazepam, temazepam or triazolam;     -   an H₁ antagonist having a sedative action, e.g. diphenhydramine,         pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;     -   a sedative such as glutethimide, meprobamate, methaqualone or         dichloralphenazone;     -   a skeletal muscle relaxant, e.g. baclofen, carisoprodol,         chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;     -   an NMDA receptor antagonist, e.g. dextromethorphan         ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan         ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine,         pyrroloquinoline quinine,         cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,         EN-3231 (MorphiDex®, a combination formulation of morphine and         dextromethorphan), topiramate, neramexane or perzinfotel         including an NR2B antagonist, e.g. ifenprodil, traxoprodil or         (−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;     -   an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,         guanfacine, dexmetatomidine, modafinil, or         4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)         quinazoline;     -   a tricyclic antidepressant, e.g. desipramine, imipramine,         amitriptyline or nortriptyline;     -   an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate         or valproate;     -   a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1         antagonist, e.g.         (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione         (TAK-637),         5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one         (MK-869), aprepitant, lanepitant, dapitant or         3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine         (2S,3S);     -   a muscarinic antagonist, e.g oxybutynin, tolterodine,         propiverine, tropsium chloride, darifenacin, solifenacin,         temiverine and ipratropium;     -   a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib,         parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;     -   a coal-tar analgesic, in particular paracetamol;     -   a neuroleptic such as droperidol, chlorpromazine, haloperidol,         perphenazine, thioridazine, mesoridazine, trifluoperazine,         fluphenazine, clozapine, olanzapine, risperidone, ziprasidone,         quetiapine, sertindole, aripiprazole, sonepiprazole,         blonanserin, iloperidone, perospirone, raclopride, zotepine,         bifeprunox, asenapine, lurasidone, amisulpride, balaperidone,         palindore, eplivanserin, osanetant, rimonabant, meclinertant,         Miraxion® or sarizotan;     -   a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist         (e.g. capsazepine);     -   a beta-adrenergic such as propranolol;     -   a local anaesthetic such as mexiletine;     -   a corticosteroid such as dexamethasone;     -   a 5-HT receptor agonist or antagonist, particularly a         5-HT_(1B/1D) agonist such as eletriptan, sumatriptan,         naratriptan, zolmitriptan or rizatriptan;     -   a 5-HT_(2A) receptor antagonist such as         R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol         (MDL-100907);     -   a 5-HT₃ antagonist, such as ondansetron     -   a cholinergic (nicotinic) analgesic, such as ispronicline         (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine         (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine         (ABT-594) or nicotine;     -   Tramadol®;     -   a PDEV inhibitor, such as         5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one         (sildenafil),         (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione         (IC-351 or tadalafil),         2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one         (vardenafil),         5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,         5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,         5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,         4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,         3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;     -   an alpha-2-delta ligand such as gabapentin, pregabalin,         3-methylgabapentin,         (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,         (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,         (3S,5R)-3-amino-5-methyl-heptanoic acid,         (3S,5R)-3-amino-5-methyl-octanoic acid,         (2S,4S)-4-(3-chlorophenoxy)proline,         (2S,4S)-4-(3-fluorobenzyl)-proline,         [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,         3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,         C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,         (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,         (3S,5R)-3-aminomethyl-5-methyl-octanoic acid,         (3S,5R)-3-amino-5-methyl-nonanoic acid,         (3S,5R)-3-amino-5-methyl-octanoic acid,         (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and         (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;     -   metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;     -   a serotonin reuptake inhibitor such as sertraline, sertraline         metabolite demethylsertraline, fluoxetine, norfluoxetine         (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine,         citalopram, citalopram metabolite desmethylcitalopram,         escitalopram, d,l-fenfluramine, femoxetine, ifoxetine,         cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine         and trazodone;     -   a noradrenaline (norepinephrine) reuptake inhibitor, such as         maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,         tomoxetine, mianserin, buproprion, buproprion metabolite         hydroxybuproprion, nomifensine and viloxazine (Vivalan®),         especially a selective noradrenaline reuptake inhibitor such as         reboxetine, in particular (S,S)-reboxetine;     -   a dual serotonin-noradrenaline reuptake inhibitor, such as         venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,         clomipramine, clomipramine metabolite desmethylclomipramine,         duloxetine, milnacipran and imipramine;     -   an inducible nitric oxide synthase (iNOS) inhibitor such as         S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,         S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,         S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,         (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic         acid,         2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile;         2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,         (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,         2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3         pyridinecarbonitrile,         2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,         N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,         or guanidinoethyldisulfide;     -   an acetylcholinesterase inhibitor such as donepezil;     -   a prostaglandin E₂ subtype 4 (EP4) antagonist such as         N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide         or         4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic         acid;     -   a microsomal prostaglandin E synthase type 1 (mPGES-1)         inhibitor;     -   a leukotriene B4 antagonist; such as         1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic         acid (CP-105696),         5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric         acid (ONO-4057) or DPC-11870, a 5-lipoxygenase inhibitor, such         as zileuton,         6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone         (ZD-2138), or         2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone (CV-6504).

Pharmaceutical compositions suitable for the delivery of compounds and salts of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in ‘Remington's Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995).

Compounds and salts of the invention intended for pharmaceutical use may be prepared and administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

Parenteral Administration

The compounds and salts of the invention may be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) and salts used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Thus, compounds and salts of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. An example of such formulations include drug-coated stents.

Topical Administration

The compounds and salts of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated [see, for example, Finnin and Morgan, J Pharm Sci, 88 (10), 955-958 (October 1999).]

Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Inhaled/Intranasal Administration

The compounds and salts of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

A pressurised container, pump, spray, atomizer, or nebuliser may contain a solution or suspension of the compound(s) or salt(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound or salt of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound or salt of the invention per actuation and the actuation volume may vary from 1 μl to 100 μl. A typical formulation may comprise a compound of formula (I) or salt thereof, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by a prefilled capsule, blister or pocket or by a system that utilises a gravimetrically fed dosing chamber. Units in accordance with the invention are typically arranged to administer a metered dose or “puff” containing from 1 to 5000 μg of the compound or salt. The overall daily dose will typically be in the range 1 μg to 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

Rectal/Intravaginal Administration

The compounds and salts of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various well known alternatives may be used as appropriate.

Ocular and Aural Administration

The compounds and salts of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid; a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose; or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

Other Technologies

The compounds and salts of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

Dosage

For administration to human patients, the total daily dose of the compounds and salts of the invention is typically in the range 0.1 mg to 200 mg depending, of course, on the mode of administration, preferred in the range 1 mg to 100 mg and more preferred in the range 1 mg to 50 mg. The total daily dose may be administered in single or divided doses.

These dosages are based on an average human subject having a weight of about 65 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

For the above-mentioned therapeutic uses, the dosage administered will, of course, vary with the compound or salt employed, the mode of administration, the treatment desired and the disorder indicated. The total daily dosage of the compound of formula (I/salt/solvate (active ingredient) will, generally, be in the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg. The total daily dose may be administered in single or divided doses. The present invention also encompasses sustained release compositions.

The pharmaceutical composition may, for example, be in a form suitable for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefor, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present invention.

It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regiments for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

For parenteral dosages, this may conveniently be prepared as a solution or as a dry powder requiring dissolution by a pharmacist, medical practitioner or the patient. It may be provided in a bottle or sterile syringe. For example it may be provided as a powder in a multicompartment syringe which allows the dry powder and solvent to be mixed just prior to administration (to aid long-term stability and storage). Syringes could be used which allow multiple doses to be administered from a single device.

The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.

In addition to the active ingredient, a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active agents. Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology.

As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.

Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative.

Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations as discussed below. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

A composition of the present invention can be administered by a variety of methods known in the art. The route and/or mode of administration vary depending upon the desired results. The active compounds can be prepared with carriers that protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are described by e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, (1978). Pharmaceutical compositions are preferably manufactured under GMP conditions.

The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.

The precise dosage administered of each active ingredient will vary depending upon any number of factors, including but not limited to, the type of animal and type of disease state being treated, the age of the animal, and the route(s) of administration.

The following non-limiting Preparations and Examples illustrate the preparation of compounds and salts of the present invention.

GENERAL EXPERIMENTAL

The Preparations and Examples that follow illustrate the invention but do not limit the invention in any way. All starting materials are available commercially or described in the literature. All temperatures are in ° C. Flash column chromatography was carried out using Merck silica gel 60 (9385). Thin layer chromatography (TLC) was carried out on Merck silica gel 60 plates (5729). “R_(f)” represents the distance travelled by a compound divided by the distance travelled by the solvent front on a TLC plate. Melting points were determined using a Gallenkamp MPD350 apparatus and are uncorrected. NMR was carried out using a Varian-Unity Inova 400 MHz NMR spectrometer or a Varian Mercury 400 MHz NMR spectrometer. Mass spectroscopy was carried out using a Finnigan Navigator single quadrupole electrospray mass spectrometer or a Finnigan aQa APCI mass spectrometer.

Where it is stated that compounds were prepared in the manner described for an earlier Preparation or Example, the skilled person will appreciate that reaction times, number of equivalents of reagents and reaction temperatures may be modified for each specific reaction, and that it may nevertheless be necessary or desirable to employ different work-up or purification conditions.

Biological Activity

Beta-Arrestin Assay

The ability of agonists to cause recruitment of beta-arrestin to the mu opioid receptor was measured using DiscoveRx PathHunter technology. A pro-linked tagged mu-opioid receptor and an EA-tagged beta-arrestin were expressed in U2OS cells and beta-arrestin recruitment measured following the methodology in McGuinness et al., 2009 (J Biomol Screen 14:49-58, Characterizing cannabinoid CB2 receptor ligands using DiscoverRx PathHunter beta-arrestin assay—McGuinness D., Malikzay A., Visconti R., Lin K., Bayne M., Monsma F., Lunn C A.)

Forskolin Stimulated cAMP

The ability of mu opioid receptor agonists to inhibit forskolin stimulated cAMP production was measured in CHO cells recombinantly expressing the mu opioid receptor, using alphascreen technology as described in Nickolls et al., 2005, with the additional inclusion of 50 uM forskolin in the assay buffer. (J Pharmacol Exp Ther 313; 1281-88, Functional selectivity of melanocortin 4 receptor peptide and non-peptide agonists: Evidence for ligand specific conformational states. Nickolls S A., Fleck B., Hoare S., Maki R.)

Functional Mu-Opioid Activity (GPI)

Functional activity at the mu-opioid receptors was determined using the electrically stimulated guinea pig isolated myenteric plexus preparation following the methodology of Hughes, J.; Kosterlitz, H. W. and Leslie, F. M. Br. J. Pharmacol. 1975, 53, 371.

Metabolic Stability

In vitro measurement of substrate metabolism can be determined using the microsomal cytochrome P450 mono-oxygenase system. This is a useful application in ranking clearance of a number of compounds by Phase I (including cytochrome P450) metabolism prior to in vivo assessment Measurement of intrinsic clearance using these methods also allows a comparison of species difference to be made to assist with translation of pharmacokinetic parameters from preclinical to clinical study.

Rat and Human Liver Microsomal Stability Assay (RLM and HLM Respectively)

Human and rat Liver microsomal assays were performed using pooled microsomes from the Pfizer Global Supply (BD Gentest™). Chemical reagents were purchased from commercial sources (Sigma-Aldrich) and drug entities synthesised at Pfizer Global Research. Incubation mixtures contained 50 mM phosphate buffer pH 7.4, 5 mM MgCl₂, 5 mM isocitric acid and 1 unit/ml isocitric dehydrogenase. The microsomes were defrosted at room temperature and sufficient volumes added to give a final concentration of 0.5 nmol cytochrome P450/ml. Following the addition of 1 μM of substrate, the incubation was pre-incubated at 37° C. for 5 minutes. The reaction was then initiated by the addition of 1 mM NADP and incubation aliquots are taken over a 1 h time course. The reaction was subsequently stopped by addition of acetonitrile cooled on ice. The incubation mixture was then centrifuged and the supernatant removed for injection onto LC-MS/MS system. Providing that the substrate concentration is below the Km, the metabolism should be first order giving a log-linear plot of substrate disappearance over time. The gradient of this line is the first order rate constant (k) and this maybe converted to estimate a substrates intrinsic clearance when factoring in the protein concentration.

The intrinsic clearance in rat or human liver microsomes is calculated from:

${{CI}_{int}\left( {{ul}\text{/}\min\text{/}{mg}\mspace{14mu}{protein}} \right)} = \frac{k \times {incubation}\mspace{14mu}{volume}}{{Protein}\mspace{14mu}{concentration}}$ Where, k=−slope of Ln concentration vs. time (min−1) Lipophilicity (LogD)

LogD octanol (pH 7.4) is a measure of lipophilicity that accounts for both hydrophobic and hydrogen-bonding interactions of a given substrate. This assay is based on shake-flask methodology, performed in a fully automated manner in a 0.1M phosphate buffer pH7.4-octanol system. Three positive controls (propranolol (logD=1.1±0.2), midazolam (logD=3.3±0.2). and amitriptyline (logD=2.7±0.2) are run with each assay.

After addition of the test substance in DMSO stock solution to the mixture and vigorous agitation followed by separation of the octanol and buffer layers by centrifugation, duplicate samples are removed from each layer and diluted prior to analysis by LC-MS/MS. Peak area is corrected for dilutions and the following equation used to calculate the logD (pH 7.4):

${{Mean}\mspace{14mu}{Log}\; D} = {{Mean}\mspace{14mu}\log_{10}\frac{\left( {{corrected}\mspace{14mu}{peak}\mspace{14mu}{area}\mspace{14mu}{for}\mspace{14mu}{octanol}\mspace{14mu}{sample}} \right)}{\left( {{corrected}\mspace{14mu}{peak}\mspace{14mu}{area}\mspace{14mu}{for}\mspace{14mu}{buffer}\mspace{14mu}{sample}} \right)}}$

The duplicate logD values must be with 0.4 log units of each other and the positive controls must be within 0.2 log units of the known logD value.

The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used:

-   APCI atmospheric pressure chemical ionisation mass spectrum -   Arbocel filter agent -   br broad -   cbz benzyloxycarbonyl -   δ chemical shift -   d doublet -   DCM dichloromethane -   dd doublet of doublets -   DMF N,N-dimethylformamide -   EDC 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride -   ES electrospray ionisation -   EtOH Ethanol -   HBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium     hexafluorophosphate -   HOBt 1-hydroxybenzotriazole monohydrate -   HPLC high pressure liquid chromatography -   hrs hours -   IBCF isobutylchloroformate -   LRMS low resolution mass spectrum -   m multiplet -   Me methyl -   MeOH Methanol -   m/z mass spectrum peak -   NMR nuclear magnetic resonance -   NMM 4-methylmorpholine -   psi pounds per square inch -   q quartet -   RM reaction mixture -   rt room (ambient) temperature -   Rt retention time -   s singlet -   SM starting material -   soln. solution -   t triplet -   TFA trifluoroacetic acid -   THF tetrahydrofuran -   tlc thin layer chromatography

For the avoidance of doubt, named compounds used herein have been named using ACD Labs Name Software v7.11™.

Where compounds are purified by HPLC, there are two methods used, shown below.

Method a Method b Column Sunfire C18 4.6 × 50 mm Xterra 4.6 × 50 mm id column id column Temperature Ambient Ambient Mobile Phase A 0.05% formic acid 0.05% ammonia in water in water Mobile Phase B 0.05% formic acid 0.05% ammonia in acetonitrile in acetonitrile Gradient - Initial 5% B 5% B Time 0 mins 5% B 5% B Time 3 mins 98% B 98% B Time 4 mins 98% B 98% B Time 4.1 mins 5% B 5% B Time 5 mins 5% B 5% B Flow rate 1.5 ml/min 1.5 ml/min Injection volume 5 ul 5 ul

EXAMPLES, PREPARATIONS, BIOLOGICAL ACTIVITY Preparation 1 N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-D-alaninamide

tert-Butyl-[(1S)-2-(D-alanylamino)-1-benzylethyl]carbamate (described in PC33903A Preparation 36; 3.43 g, 9.94 mmol) and N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosine (described in BioOrg. Med. Chem. Letts, 2003, p 599; 2.92 g, 9.25 mmol) were added sequentially to a stirred solution of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride salt (2.29 g, 11.9 mmol), 1-hydroxybenzotriazole monohydrate (1.57 g, 10.2 mmol) and N-methylmorpholine (1.01 g, 9.94 mmol) in DMF (70 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 h and then diluted with 280 mL of EtOAc and washed with 280 mL of a 10% aqueous solution of citric acid, 280 mL of water, 280 mL of a 3% aqueous solution of sodium bicarbonate, and finally 200 mL of a saturated aqueous brine solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 6.2 g (92%) of a white foam of the title compound, which was used with no further purification.

NMR (CD₃OD) 1.10 (d, 3H), 1.30 (s, 9H), 1.33 (s, 9H), 2.23 (s, 6H), 2.60-2.88 (m, 5H), 3.00-3.19 (m, 2H), 3.78-3.84 (m, 1H), 4.02-4.14 (m, 1H), 6.42 (s, 2H), 7.13-7.23 (m, 5H).

Example 1 2,6-Dimethyl-L-tyrosyl-N-[(2S)-2-amino-3-phenylpropyl]-D-alaninamide

N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}-D-alaninamide (6.1 g, 9.1 mmol) was dissolved in 25 mL dichloromethane and 25 mL TFA and stirred at room temperature for 3 h under a nitrogen atmosphere. The mixture was evaporated under reduced pressure to give a yellow gum. The gum was dissolved in 20 mL methanol and split into 4 equal portions. Each was loaded onto a separate 10 g SCX-2 cartridge, pre-wetted with methanol. Each cartridge was flushed with 50 mL of methanol to remove non-basic impurities, and then with 80 mL of 2N ammonia solution in methanol to elute the desired product. Fractions containing product were concentrated in vacuo to give a pale yellow gum. This was heated with a hot air gun and placed under vacuum (15 mm Hg) overnight to give 3.7 g (100%) of the title compound as a stiff white foam.

NMR (CD₃OD) 1.12 (d, 3H), 2.24 (s, 6H), 2.50-2.59 (m, 1H), 2.72-2.84 (m, 2H), 2.93-3.00 (m, 1H), 3.03-3.20 (m, 3H), 3.40-3.46 (m, 1H), 4.19 (q, 1H), 6.43 (s, 2H), 7.18-7.33 (m, 5H)

-   LRMS m/z (AP+): 413 [MH+] -   LogD 0.05, cLogP 1.7 -   PSA 130 -   Dofetilide binding IC₅₀>22 μM -   HLM Cl_(int) 8.4 μL/min/mg -   MDR P_(app) 0.7×10⁻⁶ cm/sec -   Mu-opioid receptor agonist IC₅₀ 9.8 nM

Preparation 2 Benzyl [(1R)-2-({(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}amino)-1-methyl-2-oxoethyl]carbamate

Benzyl-[(1R)-2-amino-1-benzylethyl]carbamate (described in J. Med. Chem., 2010, p 106; 200 mg, 0.71 mmol) and N—BOC-D-alanine (134 mg, 0.71 mmol) were added to a stirred solution of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride salt (163 mg, 0.85 mmol), 1-hydroxybenzotriazole monohydrate (115 mg, 0.75 mmol) and N-methylmorpholine (72 mg, 0.71 mmol) in DMF (3 mL) at room temperature under a nitrogen atmosphere. After 16 h the mixture was treated with 8 mL of ethyl acetate (creating a suspension) and washed with 12 mL of a 10% aqueous citric acid solution, 12 mL of water, 12 mL of a 3% aqueous solution of sodium bicarbonate, and another 10 mL of a saturated aqueous brine solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 338 mg (93%) of a white foam of the title compound, which was used with no further purification.

NMR (CD₃OD) 1.32 (d, 3H), 1.40 (s, 9H), 2.67-2.73 (m, 2H), 3.18-3.20 (m, 1H), 3.34-3.37 (m, 1H), 3.76-3.79 (m, 1H), 4.24-4.28 (m, 1H), 5.09 (s, 2H), 7.12-7.30 (m, 10H)

Preparation 3 Benzyl-[(1R)-2-(D-alanylamino)-1-benzylethyl]carbamate

Benzyl [(1R)-2-({(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}amino)-1-methyl-2-oxoethyl]carbamate (335 mg, 0.74 mmol) was dissolved in 5 mL dioxane and hydrogen chloride (4M solution in dioxane, 5 mL, 20 mmol) added and the mixture stirred at room temperature for 16 h. The mixture was evaporated under reduced pressure and the residue purified by flash column chromatography eluting with a 9:1 mixture of dichloromethane in methanol to give 150 mg (63%) of the title compound as a waxy white solid.

NMR (CD₃OD) 1.22 (d, 3H), 2.62-2.71 (m, 2H), 3.14-3.23 (m, 1H), 3.60-3.82 (m, 1H), 3.61 (m, 1H), 3.80-3.86 (m, 1H), 5.10 (s, 2H), 7.07-7.31 (m, 10H).

LRMS m/z (APCl): 356 [MH+].

Preparation 4 N-(tert-Butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-{(2R)-2-[(benzyloxycarbonyl)amino]-3-phenylpropyl}-D-alaninamide

Benzyl-[(1R)-2-(D-alanylamino)-1-benzylethyl]carbamate (145 mg, 0.41 mmol) was combined with N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosine (described in BioOrg. Med. Chem. Letts, 2003, p 599; 129 mg, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride salt (94 mg, 0.49 mmol), 1-hydroxybenzotriazole monohydrate (69 mg, 0.45 mmol) and N-methylmorpholine (42 mg, 0.41 mmol) in DMF (5 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 h and then diluted with 10 mL of EtOAc and washed with 10 mL of a 10% aqueous solution of citric acid, 10 mL of water, 10 mL of a 3% aqueous solution of sodium bicarbonate, and finally 10 mL of a saturated aqueous brine solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 243 mg (92%) of a white foam of the title compound, which was used with no further purification.

Preparation 5 N-(tert-Butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-{(2R)-2-amino-3-phenylpropyl}-D-alaninamide

N-(tert-Butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-{(2R)-2-[(benzyloxycarbonyl)amino]-3-phenylpropyl}-D-alaninamide (314 mg, 0.46 mmol) was dissolved in 5 mL of tetrahydrofuran and degassed by bubbling through argon gas for a few minutes. Palladium on charcoal (10% w/w, 5 mg) was added and the suspension stirred for 16 h at room temperature under 1 atmosphere of hydrogen pressure. The mixture was filtered through a short pad of celite, washed with 5 mL of tetrahydrofuran and evaporated under reduced pressure. The resulting residue was purified by column chromatography using 5% methanol in dichloromethane as eluant to provide the title compound as a clear oil (203 mg, 82%).

NMR (d6-DMSO) 0.98 (d, 3H), 1.30 (s, 9H), 2.23 (s, 6H), 2.60-2.88 (m, 5H), 3.00-3.19 (m, 2H), 3.88-3.92 (m, 1H), 4.02-4.14 (m, 1H), 6.34 (s, 2H), 7.13-7.23 (m, 5H).

LRMS m/z (APCl): 513 [MH+].

Example 2 2,6-Dimethyl-L-tyrosyl-N-[(2R)-2-amino-3-phenylpropyl]-D-alaninamide

N-(tert-Butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-{(2R)-2-amino-3-phenylpropyl}-D-alaninamide (203 mg, 0.36 mmol) was dissolved in 1 mL dioxane and hydrogen chloride (4M solution in dioxane, 1 mL, 4 mmol) added and the mixture stirred at room temperature for 16 h. The mixture was evaporated under reduced pressure and the residue purified by preparative HPLC and then freeze dried to provide the title compound (83 mg, 56%) as a white solid.

NMR (d6-DMSO) 0.96 (d, 3H), 2.17 (s, 6H), 2.40-2.53 (m, 1H), 2.68-2.80 (m, 2H), 2.84-2.98 (m, 1H), 3.10-3.31 (m, 3H), 3.58-3.62 (m, 1H), 4.16 (q, 1H), 6.39 (s, 2H), 7.21-7.33 (m, 5H)

LRMS m/z (APCl): 413 [MH+].

-   LogD −0.2, cLogP 1.7 -   PSA 130 -   Dofetilide binding IC₅₀>22 μM -   HLM Cl_(int)<8 μL/min/mg -   MDR P_(app) 0.6×10⁻⁶ cm/sec -   Mu-opioid receptor agonist IC₅₀ 6 nM

All publications cited in this application are each herein incorporated by reference in their entirety.

Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims. 

The invention claimed is:
 1. A compound of formula (I):

or tautomer or ionic form thereof, or a pharmaceutically acceptable salt thereof.
 2. A compound according to claim 1 of formula (Ia), (Ib), (Ic) or (Id):

or tautomer or ionic form thereof, or a pharmaceutically acceptable salt thereof.
 3. A pharmaceutical composition comprising a compound, tautomer or ionic form, according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 4. A method of treating a disease or condition indicated for treatment with an opioid receptor agonist, in a subject, by administering to a subject in need thereof a therapeutically effective amount of one or more of the compounds, tautomers, ionic forms or salt according to claim 1, or a pharmaceutically acceptable salt thereof.
 5. A pharmaceutical composition comprising a. a compound, tautomer, ionic form or salt according to claim 1; and b. a further drug substance. 